Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, causes acute infectious mononucleosis (AIM) and is linked to the development of several human malignancies. Approaches for EBV vaccine development are limited due in part to the oncogenic potential of the EBV genome and lack of animal models to test vaccine candidates. The EBV envelope glycoprotein, gp350/220, has been proposed as a vaccine antigen. However, in small Phase I/II clinical trials, vaccination with either vector constructs expressing gp350/220, or with the purified recombinant gp350 protein, did not prevent EBV infection although it did reduce the incidence of acute infectious mononucleosis (AIM) in young adults. Importantly, recombinant EBV Δgp350/220 can infect both epithelial and primary B cells in vitro. While previous studies indicate that immunity to gp350/220 can limit infection, the poor success of using gp350/220 as a single vaccine antigen calls for innovative approaches utilizing multiple EBV proteins.
At least 4 EBV gp350/220 vaccine candidates have been tested in “clinical trials” such as Vaccinia vector expressing gp350/220 (Gu et al., 1995 (Phase I-Chinese population, EBV naïve 1-3 years old children), and Recombinant gp350 in CHO cells (non-splicing variant) (3 dose regimen adjuvanted with ASO4) (Jackman et al. 1999; Moutchen et al, 2007. (Phase I/II) Safety and Immunogenicity in aged 18-37 years old EBV naïve Belgians; Sokal et al., 2007. Phase I randomized, double-blind placebo control in aged 16-25 years EBV naïve Belgians; Rees et al., 2009. Phase I chronic kidney disease kids awaiting organ transplants (UK)). However, none of these vaccine candidates achieved complete blockage of EBV infection.
Notably, EBNA1, LMP2 and gp350/220 antigens have been developed and independently tested in various clinical trials as vaccine candidates against EBV infection and EBV+ cells with promising results.
Candidate therapeutic vaccines in clinical trials include MVA-vector expressing EBNA-1 and LMP1 or LMP2 (Taylor et al., 2004 construction of the MVA vector exppressing EBNA1 and or LMP2; Hui et al., 2013-EBNA1-LMP2 (Phase I targeting NPC patients in China); Taylor et al., 2014 EBNA1-LMP2 (A Phase I Trial in UK Patients with EBV-Positive Cancer); as well as Adoptive transfer PBMCs for treatment of PTLDs and NPCs (Louis, et al., 2009, 2010, Heslop et al. 1996 T cells adoptive transfer; and Chia et al., 2012 Phase I targeting NPC patients in China. Dendritic cells are transduced with adenovirus vector expressing ΔLMP1-LMP2). A recent phase I clinical trial of recombinant modified vaccinia Ankara (MVA) vector encoding deletion of Gly-Ala regions from the EBNA1 sequence fused to LMP2 as a vaccine candidate elicited a robust EBV-specific CD4+ and CD8+ T cell response in humans. However, the strategy used to deliver these two important EBV antigens, known for their oncogenic potential, may pose major health risks, particularly in immunosuppressed individuals. Furthermore, these vaccine candidates cannot generate neutralizing antibodies to eliminate reactivation or new EBV infections. There is also a risk of vaccine tolerance since the protein is constantly produced.
Thus, there is an urgent need for EBV vaccines that are safe, prevent EBV infection and/or limit EBV disease symptoms.